GRAS Ingredients for Use in Medical Foods GRAS Ingredients for Use in Medical Foods: An Overview of FDA Regulation Ginny Bank, Cheryl Dicks, MS, RAC 1 © GRAS Associates 2016 www.gras-associates.com GRAS Ingredients for Use in Medical Foods Contents Introduction ..................................................................................................... 3 FDA Medical Food Regulation Overview ........................................................ 4 GRAS Notifications to FDA – A Review of Ingredients with Intended Use in Medical Foods ................................................................................................. 6 Ready to seek GRAS status for your medical food ingredient? ................. 11 Regulatory Services Include: ..................................................................... 11 Uncover greater market opportunities for your ingredient ......................... 12 Contact GRAS Associates today ............................................................... 12 Appendix A – Summary of GRAS Notifications Submitted to FDA for Ingredients Intended for Use in Medical Foods .......................................... 13 2 © GRAS Associates 2016 www.gras-associates.com GRAS Ingredients for Use in Medical Foods Introduction The medical food arena is a growing specialty product category that presents food and dietary supplement manufactures with interesting business opportunities for market expansion of an ingredient or final product. The Business Insights: The Emerging Market for Medical Foods Nutraceuticals World report states that the U.S. has seen over 100 new medical foods enter the marketplace since 2009. Medical foods marketing does, however, present regulatory challenges within the “gray zone” of regulation and guidance for medical foods as overseen by the Food and Drug Administration (FDA). In this article, you will learn: What products/ingredients are classified as medical foods How medical foods differ from conventional foods, dietary supplements and specialty foods Specific regulatory requirements for medical foods as overseen by the FDA What you need to do to ensure your medical food complies with the regulations The benefits of Generally Recognized as Safe (GRAS) regulatory filings for medical food ingredients Which ingredients have already achieved GRAS status in marketplace Common reasons for FDA warning letters for medical foods How to avoid getting an FDA warning letter 3 © GRAS Associates 2016 www.gras-associates.com GRAS Ingredients for Use in Medical Foods FDA Medical Food Regulation Overview A medical food, is defined in section 5(b)(3) of the 1988 Orphan Drug Act (ODA) (21 U.S.C. 360ee(b)(3)). This category is defined as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” The Agency, in 1996, published solicited comments on their advance notice of proposed rulemaking (ANPRM) for this broad category of “foods.” The ANPRM was removed in 2004 and revised as a question and answer guidance document in 2007. In 2013, FDA published a revised version of its 2007 draft guidance for medical foods, Draft Guidance for Industry: Frequently Asked Questions About Medical Foods; Second Edition. This was recently followed up with the Final Guidance on Frequently Asked Questions About Medical Foods. This revised guidance reflects FDA’s viewpoint that the statutory definition of medical foods is to be narrowly constrained to the types of products that fit within this category of food and to distinguish them from “specialty foods,” outlining the criteria. According to the final guidance, a medical food: Provides distinctive nutritional requirements, not met by alteration to normal diet; Can be foods intended for persons not able to ingest foods in certain physical forms; i.e., partial or exclusive oral intake or enteral tube feeding; Is an integral part of the patent's clinical management under medical supervision; Is intended for the "specific dietary management" of a disease or condition; 4 © GRAS Associates 2016 www.gras-associates.com GRAS Ingredients for Use in Medical Foods Is a food that is processed or specially formulated and not in its “natural” state. Furthermore, according to the FDA’s Compliance Program for Medical Foods, medical foods are classified into the following categories: a) Nutritionally complete formulas; b) Nutritionally incomplete formulas, including individual "modular" type products that may be mixed with other products before use (e.g., protein, carbohydrate, or fat modulars); c) Formulas for metabolic (genetic) disorders in patients over 12 months of age; or d) Oral rehydration products. There is much confusion around what type of food or dietary ingredient qualifies as a medical food. It is important note that medical food are NOT foods used in their “natural state” or dietary supplements simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition, and all foods fed to sick patients are not medical foods. Medical foods are foods that are specially formulated and processed for a patient who is seriously ill or who requires use of the product as a major component of a disease or condition’s specific dietary management and cannot be achieved by changes to a normal diet. In addition, medical foods must also comply with all applicable requirements for the manufacture of foods. Ingredients used in medical foods must be approved food additives or a food additive that is the subject of an exemption for investigational use (21 U.S.C. 321 and 348), if the ingredients are not Generally Recognized as Safe (GRAS). 5 © GRAS Associates 2016 www.gras-associates.com GRAS Ingredients for Use in Medical Foods GRAS Notifications to FDA – A Review of Ingredients with Intended Use in Medical Foods In an attempt to gain insight on defining the “gray zone” of medical food regulation as well as a better understanding of FDA’s viewpoint in the regulation of this category of foods which allows for permissible health and disease claims, a review of GRAS notifications to FDA, identifying medical foods as one of the food uses, is warranted. The review investigated whether the GRAS notification treated the intended use of the ingredient in medical foods differently than its use in conventional foods. A number of companies have notified FDA of GRAS determinations for ingredients with an intended use in medical foods (A summary of these ingredients is supplied in Appendix A). The majority of the ingredients were found to be sources of specific nutrients such as dietary sources of carotenoids, making up the largest number of medical food use determinations (GRN 110 and 140), minerals, fatty acids and fiber. Two submissions were for ingredients with a functional effect in the final product (e.g., sugar substitutes) and two fit neither category. Some GRAS notifications to the FDA were amended after receiving a GRN number to include medical foods as observed with the notification of tomato extract (GRN 156) and tomato pulp powder (GRN 163); specifically determining the use of these ingredients in medical foods to be GRAS. In these amendments, the notifier states that “because there is no specific deficiency, disease, syndrome or symptom arising from an absence of lycopene, the addition of lycopene, in and by itself, cannot render a food a ‘medical food’ simply as the result of its addition to the food. In this GRAS notification, tomato extract of lycopene is to be added to foods already determined to be medical foods.” The amendments also include a very detailed definition of a medical food and a detailed evaluation of the dietary 6 © GRAS Associates 2016 www.gras-associates.com GRAS Ingredients for Use in Medical Foods exposure for patients who will consume lycopene from a medical food in addition to conventional foods and dietary supplements containing lycopene. In addition, the amendments state that since medical foods are administered under supervision of a physician, it is therefore unlikely that there would be an overconsumption of lycopene. Both of the amendments received “No Questions” responses from FDA. The use of palm oil-derivedcarotenoids (GRN 320) included medical foods in the intended uses noting a specific medical food use is for the treatment of erythropoietic protoporphyria. FDA responded with a “No Questions” letter. The medical food use of selenium (GRN 260) received a “No Questions” response from FDA, for use to “facilitate avoidance of selenium deficiency to this essential micronutrient.” The notification assumes that the medical foods uses would replace 20 servings per day of traditional foods and further noted that the medical food use is to be under the supervision of a physician, intake of the ingredient would be monitored to ensure safe use. GRN 260 received a “No Questions” response from FDA. A second notification for selenium (GRN 353) also considers the use of medical foods as a supplement to the typical diet (when the medical food is not the sole source of the diet), but notes that since medical foods are administered under supervision of a physician, it is “likely that the physician is cognizant of the need for adequate amounts of selenium and the possible overdosing of selenium and therefore, will advise the patient